This thesis consists of two sections. In Section I, (pre)clinical research investigating novel targets for pre- and intraoperative molecular imaging of pancreatic cancer are discussed. In Section... Show moreThis thesis consists of two sections. In Section I, (pre)clinical research investigating novel targets for pre- and intraoperative molecular imaging of pancreatic cancer are discussed. In Section II, various studies are described which lay the groundwork for further investigation into response monitoring and prediction in rectal cancer using various imaging modalities. Show less
The aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of... Show moreThe aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of vulvar and HPV-driven diseases.Firstly, this thesis focuses on the recognition and validation of imaging-based biomarkers for recognition of diseases of the skin and external genitalia. Clinical studies were performed using 3D photography, dermatoscopy optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) on vulvar HSIL, lichen sclerosus, cutaneous warts and anogenital warts. These techniques were subsequently implemented in a clinical trial in which a novel small molecule was tested for safety and exploratory efficacy for the treatment of cutaneous warts.Furthermore, this thesis explores sequencing-based biomarkers for vulvar disease, facilitating insight into the aetiology of vulvar diseases and identifying potential new therapeutic targets. The currently available literature on the vulvar microbiome composition was investigated and expanded in an observational study characterising the vulvar microbiome composition of healthy volunteers, vulvar HSIL patients and lichen sclerosus patients. Lastly, a perspective on recent developments in the field of premalignant vulvar disease is provided, with recommendations for future applications of the biomarkers studied in this thesis. Show less
First the VG-RVPO as a monitoring for PAH in SSc patients was evaluated, here serial measurements of the VG-RVPO, can be used as a follow-up instrument to detect early changes in RV pressure over... Show moreFirst the VG-RVPO as a monitoring for PAH in SSc patients was evaluated, here serial measurements of the VG-RVPO, can be used as a follow-up instrument to detect early changes in RV pressure over time. Then we investigated the role of the VG-RVPO in improving the efficiency of the YEARS algorithm. Neither as a stand-alone diagnostic test nor when combined with the YEARS algorithm, it had any diagnostic value. Then the role of VG-RVPO in estimating the presence of PH, and the prognostic value of an abnormal VG-RVPO in PE patients was evaluated. There was an association between VG-RVPO and RV overload as measured by CTPA. In Chapter 5, the outcome of AAOCA patients is described and linked to pre-and postoperative symptoms. Overall, surgical correction significantly reduces symptoms. The CTOA on pre-and post-operative CTAs of patients with AAOCA was compared and related to anatomy and post-operative outcome. It suggests that CTA can be used to look at the anatomy of AAOCA patients before and after surgery. The last study re-evaluates the late clinical outcome and hemodynamics in patients with TOF. The findings shows, after 17.1 years there was a stabilization of RV function and an impressive durability of the homograft. Show less
This thesis focuses on health inequity in Spondyloarthritis (SpA) and potential drivers for this. The general lack of evidence on the role of socioeconomic factors, mainly at the level of the... Show moreThis thesis focuses on health inequity in Spondyloarthritis (SpA) and potential drivers for this. The general lack of evidence on the role of socioeconomic factors, mainly at the level of the individual, but also at the wider societal level, on disease outcomes in SpA, stimulated the undertaking of the individual studies described in the thesis. The possibility to study socioeconomic factors give a unique dimension to the analyses presented and provide more insights that complement the existing body of evidence. The studies presented also highlight much unmet need in our understanding of disease and in particular the intricate relationships between biological and non-biological factors that drive adverse outcomes in SpA. Many of these relationships are naturally complex and the observed effects on outcomes, multifactorial in origin. The thesis has three overarching aims, all pertaining to better understanding the role of socioeconomic factors in SpA, from different angles, both at the individual as well as the country-level and the impact on outcomes, namely imaging and work outcomes. Show less
This thesis aims to assess the differences and similarities between autoantibody-positive and autoantibody-negative RA from the start of complaints to the end of the disease. The described research... Show moreThis thesis aims to assess the differences and similarities between autoantibody-positive and autoantibody-negative RA from the start of complaints to the end of the disease. The described research was performed with the ultimate goal to clarify whether autoantibody-negative and autoantibody-positive RA are distinct diseases that require different diagnoses and treatment. Show less
Near-infrared (NIR) fluorescence imaging with indocyanine green (ICG) is a promising imaging technique for the assessment of tissue perfusion. This thesis describes the quest for valid and reliable... Show moreNear-infrared (NIR) fluorescence imaging with indocyanine green (ICG) is a promising imaging technique for the assessment of tissue perfusion. This thesis describes the quest for valid and reliable quantitative assessment of tissue perfusion using this technique, predominantly in patients with lower extremity arterial disease. Two systematic reviews were performed, describing the experience with ICG NIR fluorescence imaging within various surgical fields. In three original studies, perfusion patterns were described in various groups, including lower extremity arterial disease, healthy controls and in patients undergoing free flap reconstructive breast surgery. By applying normalization to the quantitative assessment, an increased validity and reliability was seen. To describe potential clinical applications, the use of ICG NIR fluorescence imaging was described for two indications. In patients undergoing unilateral revascularization, quantitative assessment showed an increase of inflow parameters, whilst parameters in the untreated side remained unchanged. In a cohort of patients undergoing amputation surgery, ICG NIR fluorescence imaging was able to predict postoperative skin necrosis in all four cases. Future use of ICG NIR fluorescence imaging should focus on improving validity and reliability of quantitative perfusion assessment. Show less
Venous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of... Show moreVenous thromboembolism (VTE) encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT). DVT most commonly occurs in the deep veins of the lower extremity but can also occur in the veins of upper extremity, abdomen and cerebrum. As symptoms of VTE are nonspecific, the diagnosis of VTE is based on diagnostic tests, including clinical decision rules (CDR), D-dimer tests and imaging. Although the diagnostic management of VTE has greatly advanced in recent years with the introduction of novel CDRs and high-sensitive D-dimer tests, the diagnosis may still be challenging in certain settings. The latter is mainly caused by the indirect way of thrombus visualisation by current imaging tests, such as by showing incompressibility with compression ultrasonography (CUS) or a filling defect on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI).This thesis focuses on challenging settings for diagnosing VTE, including suspected recurrent ipsilateral DVT, upper extremity DVT, cerebral vein thrombosis and portal vein thrombosis. We studied a novel imaging technique called Magnetic Resonance Non-Contrast Thrombus Imaging (MR-NCTI) and its application in these different VTE settings. Show less
In this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying... Show moreIn this thesis we have pursued innovative analytical solutions for some of the most challenging questions in the field of SpA. We have gained better insights into the concept of axSpA by studying it independently of the rheumatologist’s opinion. Our findings likely add knowledge to what axSpA really is. Future studies will learn us how much of these insights will translate into a better recognition of the disease in clinical practice and in better classifying them for research purposes. Since SpA is a slowly progressing disease, several years are needed to see meaningful changes in imaging abnormalities of the axial skeleton, which poses methodological challenges. We have shown that thoughtful analytical approaches, that make best use of imaging data, are helpful in better estimating progression, in unravelling its determinants and in clarify which outcomes are best to monitor disease. Efforts are made to further improve outcome measurement in axSpA, including the development of new imaging techniques, which can benefit from our proposed solutions to long-term imaging scoring. Show less
With tomography it is possible to reconstruct the interior of an object without destroying. It is an important technique for many applications in, e.g., science, industry, and medicine. The runtime... Show moreWith tomography it is possible to reconstruct the interior of an object without destroying. It is an important technique for many applications in, e.g., science, industry, and medicine. The runtime of conventional reconstruction algorithms is typically much longer than the time it takes to perform the tomographic experiment, and this prohibits the real-time reconstruction and visualization of the imaged object. The research in this dissertation introduces various techniques such as new parallelization schemes, data partitioning methods, and a quasi-3D reconstruction framework, that significantly reduce the time it takes to run conventional tomographic reconstruction algorithms without affecting image quality. The resulting methods and software implementations put reconstruction times in the same ballpark as the time it takes to do a tomographic scan, so that we can speak of real-time tomographic reconstruction. Show less
Despite the available treatment options and sophisticated imaging technologies for monitoring lesion development, the morbidity and mortality from acute cardiovascular events remain unacceptably... Show moreDespite the available treatment options and sophisticated imaging technologies for monitoring lesion development, the morbidity and mortality from acute cardiovascular events remain unacceptably high.While cholesterol-lowering, anti-inflammatory and anti-platelet therapies benefits can increase survival as a primary or secondary prevention, they are not sufficient for plaque rupture prevention. Moreover, the most advance imaging technologies to detect high-risk atherosclerotic patients fail to visualize and explore cellular events in small preclinical models. Therefore, there is a clear need for the development of new therapies and the application of high-resolution imaging modalities.In the current thesis, we evaluated new possibilities to inhibit and image intraplaque angiogenesis. Show less
In this thesis the focus was on diagnosing axSpA early using clinical features as well as imaging modalities. We have studied multiple elements diagnosing axSpA among patients presenting with... Show moreIn this thesis the focus was on diagnosing axSpA early using clinical features as well as imaging modalities. We have studied multiple elements diagnosing axSpA among patients presenting with chronic back pain. We have emphasized two main themes: (1) the importance of clinical SpA features; and (2) the contribution of imaging to an axSpA diagnosis and classification. We have learned how rheumatologists use imaging results in their diagnostic considerations and thereby have helped reduce certain fears regarding the way diagnosis is made in clinical practice. We have shown that the use of MRI-spine in classification is not efficient. The common thread in all of the studies in this thesis is that axSpA diagnosis is the interaction between the clinical aspects of chronic back pain and imaging findings highly suggestive of axSpA. Clinicians should be aware of mindlessly ‘stacking up’ SpA features in chronic back pain patients in order to avoid unnecessary (biologic) treatment. Additional studies are needed to investigate the numerous phenotypes of axSpA and to predict in which chronic back pain patient axSpA diagnosis is likely. Show less
The diversity in medicine and the scope of both non-invasive and invasive diagnostic instruments and treatments for ischemic heart disease have grown exponentially the last few decades. The... Show moreThe diversity in medicine and the scope of both non-invasive and invasive diagnostic instruments and treatments for ischemic heart disease have grown exponentially the last few decades. The objective of this thesis was to establish the value of different imaging techniques and treatments targeting different stages of ischemic heart disease. The results reported have demonstrated that multimodality imaging is of high relevance in patients with ischemic heart disease, facilitating the decision-making process in different groups of patients and allowing medical and (non-)invasive treatments to be better tailored to individual cases from prevention to treatment while potentially improving prognoses. Show less
Intraoperative imaging using near-infrared (NIR) fluorescence is a fast developing imaging modality as it provides real-time visual information during surgery (Chapter 1). The ability to detect... Show moreIntraoperative imaging using near-infrared (NIR) fluorescence is a fast developing imaging modality as it provides real-time visual information during surgery (Chapter 1). The ability to detect lymph nodes and tumours that need to be resected can assist the surgeon to improve surgery by reducing time of the procedure, reducing iatrogenic damage, and improve the number of radical resections. This thesis focuses on the introduction of NIR fluorescence imaging into the clinic. Part 1 of this thesis describes the optimization of NIR fluorescence imaging for sentinel lymph node (SLN) biopsy using the clinically available NIR tracer Indocyanine green (ICG) in various cancer types. Moreover, these studies show both the limitations as the clinical benefit of NIR fluorescence for SLN biopsy. Part 2 describes the use of NIR light for tumour detection. Tissue absorption and scattering in the NIR light spectrum was used for neoadjunvant treatment response monitoring in breast cancer patients. Moreover, NIR fluorescence imaging using NIR contrast agents was used for the intraoperative detection of otherwise difficult to localize liver metastases of colorectal cancer. Show less
Gold nanorods are ideal candidates for complementing fluorophores in labelling applications. The presence of the surface plasmon resonance generates large absorption and scattering cross sections,... Show moreGold nanorods are ideal candidates for complementing fluorophores in labelling applications. The presence of the surface plasmon resonance generates large absorption and scattering cross sections, thus making the detection of single nanoparticles possible under a light microscope. The plasmon of gold nanorods depends on the ratio between their width and length and covers the range between 540nm for spheres and even above 800nm for elongated particles, thus almost the entire visible and near-infrared spectrum. The surface plasmon presents great opportunities in (bio-)sensing, enhanced spectroscopies, photothermal therapy and for concentrating light below the diffraction limit. Show less
Early identification of patients with subclinical cardiovascular or cerebrovascular disease manifestation is highly relevant as organ damage might still be reversible. Imaging can be used for... Show moreEarly identification of patients with subclinical cardiovascular or cerebrovascular disease manifestation is highly relevant as organ damage might still be reversible. Imaging can be used for risk stratification and optimizing individual prevention and treatment strategies in patients with metabolic syndrome. This thesis evaluates MR and CT imaging techniques for identifying risk factors and subclinical disease in metabolic syndrome. Show less
The work described in this thesis shows how intraoperative lesion identification can be improved via the introduction of (hybrid) tracers and optimised (hybrid) imaging modalities capable... Show more The work described in this thesis shows how intraoperative lesion identification can be improved via the introduction of (hybrid) tracers and optimised (hybrid) imaging modalities capable of detecting this tracers. In part one, the reader is introduced to the concept of fluorescence image-guided surgery and the evolution thereof. Furthermore the hybrid approach for image-guided surgical guidance is presented. Part two describes the clinical evaluation of the hybrid approach using the hybrid tracer indocyanine green-technetium 99m-nanocolloid. To further refine the hybrid approach for surgical guidance, part three of this thesis describes the development and evaluation of different types of (hybrid) imaging modalities. Show less
The field of rheumatoid arthritis (RA) is moving into identification of patients as early as possible and the ultimate aim is to prevent RA becoming a chronic disease. To this end, we studied the... Show moreThe field of rheumatoid arthritis (RA) is moving into identification of patients as early as possible and the ultimate aim is to prevent RA becoming a chronic disease. To this end, we studied the phase of Clinically Suspect Arthralgia (CSA). Patients with arthralgia that were considered by the rheumatologist to have an increased risk to progress to RA (CSA) had indeed an increased risk of RA. In addition, subclinical MRI-inflammation preceded clinical arthritis with a few months. Future research will shed more light on processes underlying progression from CSA to RA and effectiveness of treatment initiation in the CSA phase. The severity of the course of RA is variable between patients and this cannot be yet accurately predicted. In this thesis, we performed studies that contributed to the understanding of these differences in severity. Three genetic risk factors for more severe joint damage progression (two non-HLA and one HLA variation) and one for arthritis persistence were identified. Further research on functional implications of the identified variants and whether they might be useful as biomarkers to guide treatment decisions is needed. Show less
This work is focussed on the precolonial Mesoamerican codices. Less than twenty of these rare books still exist today. The main questions are how were these objects made, and for what were... Show more This work is focussed on the precolonial Mesoamerican codices. Less than twenty of these rare books still exist today. The main questions are how were these objects made, and for what were they used. The author also looked at why so few of these books remain today and how they have been reproduced in more recent times. One special aspect of this research was the investigation of one specific book, the codex Añute, held at the Bodleian Libraries of the University of Oxford. This book is a known palimpsest. By understanding its physical composition, new techniques could be developed to investigate this palimpsest and recover new pictographic texts from underneath the surfaces. Show less
This thesis focuses on the assessment and monitoring of health and imaging outcomes in axial spondyloarthritis (SpA) and the relationship between these outcomes. Four major contributions to... Show more This thesis focuses on the assessment and monitoring of health and imaging outcomes in axial spondyloarthritis (SpA) and the relationship between these outcomes. Four major contributions to the understanding and management of axial SpA were made: 1) the improvement and facilitation of the assessment of disease activity using the Ankylosing Spondylitis Disease Activity Score (ASDAS), for which we defined disease activity cut-offs and response criteria and provided guidance about the calculation of the score; 2) the increase in the knowledge about the mutual relationships between health outcomes in axial SpA, namely health related quality of life, physical function, clinical disease activity, spinal mobility, structural damage and magnetic resonance imaging (MRI) of the spine; 3) the increase in the knowledge about the factors that influence phenotypic variability in axial SpA, namely Human Leukocyte Antigen B27 (HLA-B27) positivity (a genetic factor), smoking (an environmental factor) and the presence of psoriasis (an extra-articular manifestation); and 4) the insight into the processes that drive structural progression in axial SpA and into the link between inflammation and structural damage, by specifically looking at the relationship between MRI inflammation, MRI fat deposition and new bone formation in axial SpA. Show less
De belangrijkste resultaten van dit proefschrift: de ASAS classificatie criteria voor axSpA blijken robuust en zijn goed toepasbaar in een setting waarbij de waarschijnlijkheid op axSpA lager is... Show moreDe belangrijkste resultaten van dit proefschrift: de ASAS classificatie criteria voor axSpA blijken robuust en zijn goed toepasbaar in een setting waarbij de waarschijnlijkheid op axSpA lager is dan waarin de criteria ontwikkeld zijn. Daarnaast is er op basis van bevindingen in dit proefschrift een belangrijke aanpassing doorgevoerd in een hulpmiddel dat reumatologen begeleidt in het diagnostische proces van (vroege) axSpA. Tevens is het MRI protocol van het SPACE cohort aangepast nadat de toegevoegde waarde van het toedienen van een contrastvloeistof bij het maken van MRI’s nihil bleek te zijn, met als resultaat dat er sinds april 2012 geen MRI’s meer worden gemaakt met de toediening van gadolinium. Dit proefschrift biedt ook adequate handvatten voor verder onderzoek naar de optimale definitie van een positieve MRI. Bovendien worden discrepanties aangaande de beoordeling door verschillende soorten lezers van afwijkingen in de rug (op röntgenfoto’s en MRI’s) aan het licht gebracht waardoor de vraag naar voren komt of training in het onderscheiden van axSpA afwijkingen en afwijkingen die niet gerelateerd zijn aan axSpA van potentiële belang is op de betrouwbaarheid van het beoordelen van afwijkingen in de rug. De onderzoeken in dit proefschrift leveren een bijdrage aan betere herkenning en behandeling van axSpA. Show less
